Marine neurotoxins

RCM was also used in Yamamoto s total synthesis of the marine neurotoxin gambierol (81) [62], to close the central seven-membered E ring, thereby completing the octacyclic polyether core 80 (Scheme 15). Following previously developed methodology [63], metathesis precursor 79 was produced as the major epimer, by boron trifluoride etherate-mediated intramolecular allylation of a-chloroacetoxy ether 78. Subsequent treatment of 79 with catalyst C produced the octacyclic ether 80 in 88% yield. 

Scheme 15 Formation of the central rings D and E by sequential intramolecular allylation and RCM in Yamamoto s total synthesis of the marine neurotoxin gambierol (81) [62]...

Intramolecular allylation of a-chloroacetoxy ether 185 followed by RCM (Scheme 35) was used by Yamamoto and coworkers to construct the eight-membered cyclic ether in the F-K ring segment 186 of the marine neurotoxin brevetoxin B (184) [91]. 

Scheme 34 Formation of the central nine-membered ring and completion of the carbon skeleton in Hirama s improved total synthesis of the marine neurotoxin ciguatoxin CTX3C (183)[90b]...

Hardstafe WR, Jamieson WD, Milley JE, Quilliam MA, Sim PG (1990) Reference materials for domoic acid, a marine neurotoxin. Fresenius J Anal Chem 338 520-525. 

Reductive cleavage of the thiazoline C-S bond in heterocycle 193 with -Bu3SnH <1986T3537> followed by in situ hydrolysis of the resulting hemiaminal and protection of nitrogen as its benzyl carbamate gave 194 in 64% overall yield. This was then converted in several steps to potent marine neurotoxin Kainic acid 195 in racemic form (Scheme 27) <1994JOC2773>. 

This article will outline firstly the application of RCM technology to the preparation of the epothilones with particular emphasis on the generality and mild nature of the process. The second section will describe the use of cyclopentadi-enyl titanium reagents in metathesis processes and, in particular, their application to the preparation of polyether segments of marine neurotoxins. 

Wu, C.H. and Narahashi, T., Mechanism of action of novel marine neurotoxins on ion channels, Annu. Rev. Pharmacol. Toxicol., 28, 141, 1988. 

Stommel, E. W. and Watters, M. R. (2004). Marine neurotoxins Ingestible toxins. Curr. Treat. Options Neurol. 6,105-114. 

In the synthesis of the marine neurotoxin hemibrevetoxin B 121, dienetriol 119 was used as an RCM substrate for elaboration of the seven-membered A ring in 121 (Scheme 21). While catalyst B was ineffective in this case, the ring closure occurred smoothly with catalyst G providing the tetracyclic intermediate 120 in high yield. 

RCM was also used in Yamamoto s synthesis of the marine neurotoxin gambierol to close the... 

M.A. Quilliam, B.A. Thomson, G.J. Scott and K.W.M. Siu, Ion-spray mass spectrometry of marine neurotoxins, Rapid Commun. Mass Spectrom., 3, 145-150 (1989). 

Ryan, J.C., Morey, J.S., Ramsdell, J.S., and VanDolah, EM. 2005. Acute phase gene expression in mice exposed to the marine neurotoxin domoic acid. Neuroscience. 

The synthesis of the marine neurotoxin ciguatoxin CTX3C (Section 20.7)... 

No risk factors for illness have been identihed other than estimated ingested dose [162], The investigation in North Carolina examined age, gender, the presence of chronic illness, medication use, and alcohol consumption during the implicated meal and fonnd no association with illness. As with other marine neurotoxins, brevetoxin is heat stable and thus, cooking contaminated seafood will not alter the risk of intoxication. Furthermore, the toxin is lipid rather than water-soluble [174] and thus, boiling or steaming contaminated food is similarly unlikely to alter the risk of intoxication. 

Quilliam, M. A., et al. High-performance liquid chromatography of domoic acid, a marine neurotoxin, with application to shellfish and plankton. Intern. J. Environ. Anal. Chem., 36, 139-154 (1989). 

Washburn, B. S., Rein, K. S., Baden, D. G. et al., Brevetoxin-6 (PbTx-6), a nonaromatic marine neurotoxin, is a ligand of the aryl hydrocarbon receptor. Arch. Biochem. Biophys. 343, 149, 1997. 

Marine Neurotoxins Targeting Voltage-Gated Ion Channels. 892... 

MARINE NEUROTOXINS TARGETING VOLTAGE-GATED ION CHANNELS... 

Stommel (2004). Stommel EW, Watters MR. Marine neurotoxins ingestible toxins. Curr Treat Options Neurol 2004 6 105-114. 

Watters (1999). Watters MR, Cannard KR. Marine neurotoxins. In Chopra JS, Sawhney IMS (eds). Neurology in Tropics, B I Churchill Livingstone, New Delhi, 1999 45-68. 

Watters (2005). Watters MR. Tropical marine neurotoxins venom to dmgs. Sem Neurol 2005 25(3) 278-289. 

Figure 9 A stereo view of a superposition of two marine neurotoxins, saxitoxin (8 dashed line) and tetrodotoxin (9), using the method of Danzinger and Dean. The atoms superimposed are shown in bold.

Dean and Chau have used this method to measure the similarity of the accessible and molecular electrostatic potential surfaces of two marine neurotoxins. One superposition used the rms value of eight atoms.In this orientation, the electrostatic potential surfaces were found to have a rank correlation coefficient of approximately 0.8. In a different superposition, the surfaces were compared to determine orientations that give maximal correspondence of the surface property. " Here, several superimpositions, illuminating the relatively high degree of similarity between the accessible surfaces of these dissimilar molecules, were found. 

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